Neuromotor disorders such as spinal cord injury (SCI) and stroke lead to distinct impairments of motor pattern generation and balance (Courtine, G., et al. Transformation of nonfunctional spinal circuits into functional states after the loss of brain input. Nat Neurosci 12, 1333-1342 (2009); Harkema, S. J., et al. Human lumbosacral spinal cord interprets loading during stepping. J Neurophysiol 77, 797-811, 1997).
A large number of studies have investigated the ability of agonists and antagonists to specific monoaminergic receptors to engage spinal locomotor networks after the interruption of descending pathways.
In particular, the function of α2 adrenergic receptors subtypes in the production of locomotion by the spinal neuronal circuitries engaged through electrical stimulation after spinal cord injury (SCI) has been investigated.
The α2 adrenergic agonist clonidine is known to induce a marked facilitation of locomotion in cats with a complete spinal cord injury (SCI) (Barbeau, Chau and Rossignol, Noradrenergic agonists and locomotor training affect locomotor recovery after cord transection in adult cats. 1993. Brain Res Bull; 30(3-4):387-93). Also the work of Domingo et al. (Domingo, Al-Yahya A A, Asiri Y, Eng J J, Lam T; Spinal Cord Injury Rehabilitation Evidence Research Team. A systematic review of the effects of pharmacological agents on walking function in people with spinal cord injury. J Neurotrauma. 2012 Mar. 20; 29(5):865-79. doi: 10.1089/neu.2011.2052) shows that α2 adrenergic receptor agonists clonidine and tizanidine facilitated expression of locomotion in spinalized cats.
The development of drugs engaging the α2 adrenergic system for facilitating locomotion and neurorehabilitation in humans with SCI is therefore an object of study. However, application of these pharmacological agents in humans with SCI has yielded conflicting results. For example, in human, clonidine injections dysfacilitated locomotion (Dietz V, Colombo G, Jensen L, Baumgartner L. Locomotor capacity of spinal cord in paraplegic patients. Ann Neurol. 1995 May; 37(5):574-82). In the same line, clonidine abolished stepping in rats with complete SCI (Controlling specific locomotor behaviors through multidimensional monoaminergic modulation of spinal circuitries. Musienko P, van den Brand R, Marzendorfer O, Roy R R, Gerasimenko Y, Edgerton V R, Courtine G. J Neuroscience 2011 Jun. 22; 31(25):9264-78).
Some works have shown that the α2 adrenergic receptor subtypes predominating in the rat spinal cord are α2a and α2c (Giroux N, Rossignol S, Reader T A. Autoradiographic study of alpha1- and alpha2-noradrenergic and serotonin1A receptors in the spinal cord of normal and chronically transected cats. J Comp Neurol. 1999 Apr. 12; 406(3):402-14; Puke M J, Luo L, Xu X J. The spinal analgesic role of alpha 2-adrenoceptor subtypes in rats after peripheral nerve section. Eur J Pharmacol. 1994 Aug. 1; 260(2-3):227-32).
However, the exact function of the different α2 receptors subtypes in the production of locomotion is still unclear. WO200203918 discloses the use of β2-agonists for recovering locomotive functions and/or neuromuscular strength following spinal cord injuries. An adrenergic receptor is targeted but different from the α2.
US2011160253 discloses deuterated Tizanidine for treating diseases and conditions that are beneficially treated by administering an α2-adrenoceptor agonist. In particular, the activity of said receptors is modulated in a cell of the central nervous system. Among the possible diseases to be cured, muscle hypertonia and muscle spasticity associated with SCI is cited. However, no specific targeting of selected adrenergic receptor subtypes is mentioned in the document and no reference is made to recovering locomotive function.
In US2011160265 an α2 receptor agonist lacking significant α-2a receptor activity is used for treating motor disorders. In particular, the α-2 receptor agonist can be an α2c receptor agonist. Spinal cord disorders, as SCI, are not listed among the motor disorders which can be treated.
In US20050059664 α-2a/α-1a selective agonists are administered for preventing or alleviating a neurological condition, where said condition can be a spinal cord trauma. However, this reference is mainly directed to the treatment of neurological pain. Locomotor activity is mentioned, but only in relation to the sedative effect of the drugs.
US2003139422 discloses use of an agonist of 5HT receptor and a β2-adrenenergic agonist for inhibiting muscular degeneration in an individual suffering from spinal cord injury.
Combinations of agonists/antagonists of specific α2 receptor subtypes have been disclosed in some patent documents, however only for applications other than neuromotor disorders.
For example, in EP2351561 it is provided a method of alleviating pain in a subject by administering to the subject a pharmaceutical composition containing an effective amount of an α-adrenergic agonist and a pharmaceutical composition containing an effective amount of a selective α-2a antagonist. Also WO2007057508 discloses the use of α2-adrenoceptor antagonists to augment the action of a μ-opioid receptor agonist for the treatment of pain, which pain can, among others, be caused by spinal cord injury or other damage of the spinal cord.
In US2009202518 a method for inhibiting an inflammatory response in a mammal comprising treating the mammal with an α2a adrenergic antagonist is disclosed.
A further example is US20060293359, wherein an α2 agonist composition is disclosed which may comprise an α2 agonist (either an α2b or 2c selective agonist or an α2 pan-agonist) having activity at the α2b and/or α2c adrenergic receptor subtypes plus comprising an additional component selected from the group consisting of an al receptor antagonist or an α2A receptor antagonist or both. Said composition is disclosed for treating symptoms of diabetes.
The identification of the specific α2 receptor subtypes involved in the production of locomotion as well as their specific effective targeting for the treatment of spinal cord motor disorders is still missing.
Therefore, there is still the need of a pharmacological treatment of spinal cord motor disorders in order to efficaciously improve and restore locomotion.